The deubiquitinase OTUB1 augments NF-κB-dependent immune responses in dendritic cells in infection and inflammation by stabilizing UBC13

查看全文 作　　者：Floriana [1,2]Mulas;Xu [1,2,3]Wang;Shanshan [1]Song;Gopala [1,2]Nishanth;Wenjing [1,2]Yi;Anna [4]Brunn;Pia-Katharina [5]Larsen;Berend [6]Isermann;Ulrich [5,7]Kalinke;Antonio [8]Barragan;Michael [9]Naumann;Martina [4]Deckert;Dirk [1,2,7]Schlüter

机构地区：[1]Institute of Medical Microbiology and Hospital Hygiene,Otto-von-Guericke University Magdeburg,39120,Magdeburg,Germany;[2]Institute of Medical Microbiology and Hospital Epidemiology,Hannover Medical School,30625,Hannover,Germany;[3]Chemical Biology Research Center,School of Pharmaceutical Sciences,Wenzhou Medical University,325035,Wenzhou,China;[4]Department of Neuropathology,Faculty of Medicine and University Hospital Cologne,University of Cologne,50931,Cologne,Germany;[5]Institute for Experimental Infection Research,TWINCORE Centre for Experimental and Clinical Infection Research,a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research,30625,Hannover,Germany;[6]Institute for Clinical Chemistry and Pathobiochemistry,Otto-von-Guericke University Magdeburg,39120,Magdeburg,Germany;[7]Cluster of Excellence-Resolving Infection Susceptibility(RESIST),Hannover Medical School,30625,Hannover,Germany;[8]Department of Molecular Biosciences,Stockholm University,10691,Stockholm,Sweden;[9]Institute for Experimental Internal Medicine,Otto-von-Guericke University Magdeburg,39120,Magdeburg,Germany

出　　处：《Cellular & Molecular Immunology》索引2021年第18卷第6期,共16页

基　　金：funded by the Deutsche Forschungsgemeinschaft(DFG,German Research Foundation)-Project-ID 97850925-SFB 854(project TP5 to M.N.and DS),Project-ID 406922110-Joint French-German Project cGASVAC(to U.K.);Project-ID 158989968-SFB900(project B2 to U.K.)。 摘　　要：Dendritic cells(DCs)are indispensable for defense against pathogens but may also contribute to immunopathology.Activation of DCs upon the sensing of pathogens by Toll-like receptors(TLRs)is largely mediated by pattern recognition receptor/nuclear factor-κB(NF-κB)signaling and depends on the appropriate ubiquitination of the respective signaling molecules.However,the ubiquitinating and deubiquitinating enzymes involved and their interactions are only incompletely understood.Here,we reveal that the deubiquitinase OTU domain,ubiquitin aldehyde binding 1(OTUB1)is upregulated in DCs upon murine Toxoplasma gondii infection and lipopolysaccharide challenge.Stimulation of DCs with the TLR11/12 ligand T.gondii profilin and the TLR4 ligand lipopolysaccharide induced an increase in NF-κB activation in OTUB1-competent cells,resulting in elevated interleukin-6(IL-6),IL-12,and tumor necrosis factor(TNF)production,which was also observed upon the specific stimulation of TLR2,TLR3,TLR7,and TLR9.Mechanistically,OTUB1 promoted NF-κB activity in DCs by K48-linked deubiquitination and stabilization of the E2-conjugating enzyme UBC13,resulting in increased K63-linked ubiquitination of IRAK1(IL-1 receptor-associated kinase 1)and TRAF6(TNF receptor-associated factor 6).Consequently,DC-specific deletion of OTUB1 impaired the production of cytokines,in particular IL-12,by DCs over the first 2 days of T.gondii infection,resulting in the diminished production of protective interferon-γ(IFN-γ)by natural killer cells,impaired control of parasite replication,and,finally,death from chronic T.encephalitis,all of which could be prevented by low-dose IL-12 treatment in the first 3 days of infection.In contrast,impaired OTUB1-deficient DC activation and cytokine production by OTUB1-deficient DCs protected mice from lipopolysaccharide-induced immunopathology.Collectively,these findings identify OTUB1 as a potent novel regulator of DCs during infectious and inflammatory diseases. 关键词：OTUB1 dendritic cell signal transduction UBIQUITINATION innate immunity

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The deubiquitinase OTUB1 augments NF-κB-dependent immune responses in dendritic cells in infection and inflammation by stabilizing UBC13

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